This invention relates to the field of pharmaceutical and organic chemistry and provides naphthalene compounds, intermediates, formulations, and methods.
Osteoporosis describes a group of diseases which arises from diverse etiologies, but which are characterized by the net loss of bone mass per unit volume. The consequence of this loss of bone mass and resulting bone fracture is the failure of the skeleton to provide adequate support for the body. One of the most common types of osteoporosis is associated with menopause. Most women lose from about 20% to about 60% of the bone mass in the trabecular compartment of the bone within 3 to 6 years after the cessation of menses. This rapid loss is generally associated with an increase of bone resorption and formation. However, the resorptive cycle is more dominant and the result is a net loss of bone mass. Osteoporosis is a common and serious disease among postmenopausal women.
There are an estimated 25 million women in the United States alone who are afflicted with this disease. The results of osteoporosis are personally harmful, and also account for a large economic loss due to its chronicity and the need for extensive and long term support (hospitalization and nursing home care) from the disease sequelae. This is especially true in more elderly patients. Additionally, although osteoporosis is generally not thought of as a life threatening condition, a 20% to 30% mortality rate is related to hip fractures in elderly women. A large percentage of this mortality rate can be directly associated with postmenopausal osteoporosis.
The most generally accepted method for the treatment of postmenopausal osteoporosis is estrogen replacement therapy. Although therapy is generally successful, patient compliance with the therapy is low, primarily because estrogen treatment frequently produces undesirable side effects. An additional method of treatment would be the administration of a bisphosphonate compound, such as, for example, Fosomax(copyright) (Merck and Co., Inc.).
Throughout premenopausal time, most women have less incidence of cardiovascular disease than men of the same age. Following menopause, however, the rate of cardiovascular disease in women slowly increases to match the rate seen in men. This loss of protection has been linked to the loss of estrogen and, in particular, to the loss of estrogen""s ability to regulate the levels of serum lipids. The nature of estrogen""s ability to regulate serum lipids is not well understood, but evidence to date indicates that estrogen can up regulate the low density lipid (LDL) receptors in the liver to remove excess cholesterol. Additionally, estrogen appears to have some effect on the biosynthesis of cholesterol, and other beneficial effects on cardiovascular health.
It has been reported in the literature that serum lipid levels in postmenopausal women having estrogen replacement therapy return to concentrations found in the premenopausal state. Thus, estrogen would appear to be a reasonable treatment for this condition. However, the side effects of estrogen replacement therapy are not acceptable to many women, thus limiting the use of this therapy. An ideal therapy for this condition would be an agent which regulates serum lipid levels in a manner analogous to estrogen, but which is devoid of the side effects and risks associated with estrogen therapy.
Another major estrogen associated pathology is estrogen-dependent breast cancer and, to a lesser extent, estrogen-dependent cancers of other organs, particularly the uterus. Although such neoplasms are not solely limited to a postmenopausal woman, they are more prevalent in the older, postmenopausal population. Current chemotherapy of these cancers have relied heavily on the use of anti-estrogen compounds, such as tamoxifen. Although such mixed agonist-antagonists have beneficial effects in the treatment of these cancers, and the estrogenic side-effects are tolerable in acute life-threatening situations, they are not ideal. For example, these agents may have stimulatory effects on certain cancer cell populations in the uterus due to their estrogenic (agonist) properties and they may, therefore, be counterproductive in some cases. A better therapy for the treatment of these cancers would be an agent which is an antiestrogenic compound having fewer or no estrogen agonist properties on reproductive tissues.
Thus, it would be a significant contribution to the art to provide novel compounds useful, for example, in the treatment or prevention of the disease states as indicated herein.
The present invention relates to compounds of formula I 
wherein
R1 is xe2x80x94H, xe2x80x94OH, xe2x80x94O(C1-C4 alkyl), xe2x80x94OCO(C1-C6 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94O(C1-C6 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94Ar, xe2x80x94OSO2(C2-C6 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94OAr, where Ar is optionally substituted phenyl;
R2 is xe2x80x94H, xe2x80x94Cl, xe2x80x94F, C1-C4 alkyl, xe2x80x94OH, xe2x80x94O(C1-C4 alkyl), xe2x80x94OCO(C1-C6 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94O(C1-C6 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94Ar, xe2x80x94OSO2(C2-C6 alkyl), or xe2x80x94Oxe2x80x94COxe2x80x94OAr, where Ar is optionally substituted phenyl;
R3 and R4 are, independently, R2, with the proviso that R3 and R4 are not both hydrogen.
R5 is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino; and
n is 2 or 3;
or a pharmaceutically acceptable salt or solvate thereof.
The present invention further relates to intermediate compounds of formula II which are useful for preparing the pharmaceutically active compounds of the present invention, and are shown below: 
wherein
R1a is xe2x80x94H or xe2x80x94OR6 in which R6 is a hydroxy protecting group;
R2a, R3a, and R4a are, independently, xe2x80x94H, xe2x80x94Cl, xe2x80x94F, C1-C4 alkyl, xe2x80x94OR6 in which R6 is a hydroxy protecting group;
n and R5 have their previous meanings;
and further, wherein said compound is in the Zxe2x80x94 or Exe2x80x94 stereoisomeric form, and mixtures thereof.
Further, the present invention provides intermediate compounds of formula III which are useful for preparing the pharmaceutically active compounds of the present invention, and are shown below. 
wherein
R1a, R2a, R3a, R4a, R5, and n have their previous meanings and provisions; and
R7 is xe2x80x94OH or xe2x80x94OR8, where R8 is a C1-C6 alkyl sulfonyl or aryl sulfonyl.
The present invention further provides intermediate compounds of formula IX which are useful for preparing the pharmaceutically active compounds of the present invention, and are shown below: 
wherein:
R1a, R2a, R3a, R4a, R5, and n have their previous meanings and provisions.
The present invention further relates to pharmaceutical compositions containing compounds of formula I.
Still further, the current invention provides methods for the therapeutic use of such compounds and compositions.
General terms used in the description of compounds herein described bear their usual meanings. For example, xe2x80x9cC1-C6 alkylxe2x80x9d refers to straight or branched aliphatic chains of 1 to 6 carbon atoms including moieties such as methyl, ethyl, propyl, isopropyl, butyl, n-butyl, pentyl, isopentyl, hexyl, isohexyl, and the like. Similarly, the term xe2x80x9cxe2x80x94OC1-C4 alkylxe2x80x9d represents a C1-C4 alkyl group attached through an oxygen molecule and include moieties such as, for example, methoxy, ethoxy, n-propoxy, isopropoxy, and the like. Of these alkoxy groups, methoxy is highly preferred in most circumstances.
Optionally substituted phenyl includes phenyl and phenyl substituted once or twice with C1-C6 alkyl, C1-C4 alkoxy, hydroxy, nitro, chloro, fluoro, or tri (chloro or fluoro)methyl.
The term, xe2x80x9chydroxy protecting groupxe2x80x9d contemplates numerous functionalities used in the literature to protect a hydroxyl function during a chemical sequence and which can be removed to yield the phenol. Included within this group would be acyls, mesylates, tosylates, benzyl, alkylsilyloxys, xe2x80x94OC1-C4 alkyls, and the like. Numerous reactions for the formation and removal of such protecting groups are described in a number of standard works including, for example, Protective Groups in Organic Chemistry, Plenum Press (London and New York, 1973); Green, T. W., Protective Groups in Organic Synthesis, Wiley, (New York, 1981); and The Peptides, Vol. I, Schrooder and Lubke, Academic Press (London and New York, 1965). Methods for removing preferred R6 hydroxy protecting groups, particularly methyl, are essentially as described in Example 2, infra.
The term xe2x80x9cinhibitxe2x80x9d includes its generally accepted meaning which includes prohibiting, preventing, restraining, alleviating, ameliorating, and slowing, stopping or reversing progression, severity, or a resultant symptom. As such, the present method includes both medical therapeutic and/or prophylactic administration, as appropriate.
The starting material for preparing compounds of the present invention is a compound of formula IV 
wherein
R1a is xe2x80x94H or xe2x80x94OR6 in which R6 is a hydroxy protecting group, preferred is methyl.
Compounds of formula IV are known in the art and are prepared essentially as described by Jones et al., in U.S. Pat. No. 4,400,543 and Jones et al., in U.S. Pat. No. 5,147,880 each of which are herein incorporated by reference. See, also, Jones et al., J. Med. Chem., 35:931-8 (1992) and Jones et al., J. Med. Chem., 22:962 (1979).
In preparing compounds of the present invention, generally, a 1-acylated-2-tetralone of formula IV (written in its enolic form) is treated with a base to form its corresponding anion, which is reacted with diphenylchlorophosphate, providing an enol phosphate derivative of formula V. The formula V compound undergoes formal addition-elimination when treated with an aryl Grignard reagent (VI), which results in substitution of the 2-phosphate substituent by the aryl moiety, thereby producing a compound of formula VII. Dealkylation of a formula VII compound by a thiolate anion demethylation reagent selectively dealkylates the group which is located para to the electron-withdrawing carbonyl group. The result of such selective dealkylation is a phenolic compound of formula VIIxe2x80x2, which serves as an intermediate to the compounds of this invention. This synthetic route is as shown below in Scheme I, and R1a, R2a, R3a, and R4a have their previous meanings and provisions. 
In particular, a formula IV enolic compound is phosphorylated by one or more equivalents of a phosphorylating reagent which is a diarylchloro- or diarylbromo-phosphate and preferably diphenylchlorophosphate. This reaction, may be carried out in a variety of inert solvents including ethers, THF, dioxane, ethyl acetate, toluene, and acetonitrile and in the presence of a strong base such as an alkali metal hydride, alkali metal hydroxide, or alkali metal carbonate or a trialkyl amine such as triethyl amine. The alkali metal base or tertiary amine acts as a basic catalyst in the phosphorylation process. Although it is preferable to run the reaction at ice bath temperature so as to avoid unwanted side products, elevated temperatures can also be used, but they are usually unnecessary to complete the phosphorylation reaction. The product of the phosphorylation reaction, an enol phosphate derivative of formula V may be isolated by usual techniques, such as chromatography. However, it is most convenient to generate the enolphosphate using a solvent/acid scavenger combination which is compatable with the next step of the reaction (additon of a Grignard Reagent). Thus, the combination of sodium hydride in THF under a nitrogen atmosphere is preferred, and leads to a rapid phosphorylation providing a compound of formula V.
The intermediate enol phosphate (V), either isolated or generated in situ, may then be reacted with one or more equivalents of an aryl Grignard reagent or an aryl lithium organocuprate reagent. One to two equivalents of an aryl magnesium bromide (VI) is preferred. Such Grignard reagents would include, but are not limited to: 3-methoxyphenyl magnesium bromide, 3-chlorophenyl magnesium bromide, 2-methoxyphenyl magnesium bromide, 3-fluorophenyl magnesium bromide, 3-methylphenyl magnesium bromide, 2-methylphenyl magnesium bromide, 2-methyl-3-methoxyphenyl magnesium bromide, 3-methoxy-4-fluorophenyl magnesium bromide, 2-chloro-4-methoxyphenyl magnesium bromide, 3,4-dimethoxyphenyl magnesium bromide, 3-fluoro-4-methoxyphenyl magnesium bromide, and the like. The reaction is typically conducted at ice bath temperatures to minimize side reactions, but elevated temperatures can be used to increase the rate of the reaction. The addition of the aryl moiety, followed by the elimination of the phosphate leaving group (formally a 1,4-addition, elimination process) gives rise to a dihydronaphthalene derivative of formula VII, which may then be isolated by conventional techniques such as crystallization or chromatography.
The resulting dihydronaphthalene derivative of formula VII is then demethylated to provide an intermediate of formula VIIxe2x80x2 which completes the chemical sequence as shown in Scheme I. In order to accomplish regioselective demethylation at the methoxy group para to the carbonyl, a nucleophilic demethylation reagent is used, and alkali metal thiolates (alkali metal salt of an organic thiol) are preferred. Especially preferred are lithium thioethylate or lithium thiomethylate, in excess to the extent of 1.2 or more equivalents of the demethylation reagent over the substrate. The reaction is conducted under an inert atmosphere to preserve the demethylation reagent and in a solvent which is practically inert to the nucleophilic nature of the thiolate reagent. Suitable solvents for the demethylation are those which are most conducive to bimolecular nucleophilic displacement reactions, and these include dimethylsulfoxide dimethylformamide, dimethylacetamide, and THF. Anhydrous dimethylformamide is preferred. In order to simultaneously achieve a satisfactory reaction rate and also obtain good control of the selectivity for demethylation at the site para to the carbonyl group, it is important to carefully control the temperature of the reaction. Although the demethylation process will take place in the range of temperatures from 60xc2x0 C. to 120xc2x0 C., it is advantageous to use a temperature in the range of 80xc2x0-90xc2x0 C. to optimize the yield of the desired product. A temperature of 80xc2x0 C. is particularly preferred. Under the preferred reaction conditions, the transformation from a formula VII compound to a formula VIIxe2x80x2 compound is complete after heating for about 2 to 4 hours at the indicated temperature.
Compounds of formula VII and VIIxe2x80x2 collectively are novel intermediates which are useful for the preparation of pharmaceutically active compounds of formula I of the present invention. Compounds of formula VII and VIIxe2x80x2 would include, but not be limited to:
[2-(3-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-methoxyphenyl]methanone
[2-(3-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-hydroxyphenyl]methanone
[2-(3-methoxyphenyl)-3,4-dihydro-naphthalen-1-yl][4-methoxyphenyl]methanone
[2-(3-methoxy-4-methylphenyl)-3,4-dihydro-naphthalen-1-yl][4-hydroxyphenyl]methanone
[2-(2-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-methoxyphenyl]methanone
[2-(3,4-di-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-methoxyphenyl]methanone
[2-(3,4-di-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-hydroxyphenyl]methanone
[2-(3-chlorophenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-methoxyphenyl]methanone
[2-(2-methoxy-3-fluorophenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-methoxyphenyl]methanone
[2-(2-methyl-2-methyl-3-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-hydroxyphenyl]methanone
[2-(3-methoxy-4-fluorophenyl)-3,4-dihydro-naphthalen-1-yl][4-methoxyphenyl]methanone
[2-(2-chloro-3-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-hydroxyphenyl]methanone
[2-(2-ethyl-4-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-hydroxyphenyl]methanone
[2-(2,4-dimethyl-3-methoxyphenyl)-3,4-dihydro-naphthalen-1-yl][4-methoxyphenyl]methanone
[2-(2-chloro-3-methoxy-4-fluorophenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-hydroxyphenyl]methanone
Upon preparation of a formula VIIxe2x80x2 compound, it is reacted with a compound of formula VIII
R5xe2x80x94(CH2)nxe2x80x94Qxe2x80x83xe2x80x83VIII
wherein R5 and n are as defined above and Q is a bromo or, preferably, a chloro moiety, or a salt thereof, to form a compound of formula IXxe2x80x2. The formula IXxe2x80x2 compound may be deprotected, when R6 hydroxy protecting groups are present, to form a compound of formula IXxe2x80x3. These process steps are shown in Scheme III below. 
wherein
R1a-4a, n, and R5 have their previous meanings and provisions;
R1b is xe2x80x94H, xe2x80x94OH, or xe2x80x94OCH3;
R2b, R3b, and R4b are, independently, xe2x80x94H, xe2x80x94Cl, xe2x80x94F, xe2x80x94OH, xe2x80x94OCH3, or C1-C4 alkyl, with the proviso that R3b and R4b are not both hydrogen;
or a pharmaceutically acceptable salt or solvate thereof.
In the first step of the process shown in Scheme II, the alkylation is carried out via standard procedures. Compounds of formula VIII are commercially available or are prepared by means well known to one of ordinary skill in the art. Compounds of formula VIII would include, but not be limitd to: 1-(2-chloroethyl)piperidine hydrochloride, 1-(2-chloroethyl)pyrrolidine hydrochloride, 1-(2-chloroethyl)hexamethyleneimino hydrochloride, 1-(3-chloropropyl)piperidine hydrochloride, 1-(3-chloropropyl)-2-methylpyrrolidine hydrochloride, 2-chloroethyl-N,N-dimethylamine hydrochloride, 3-chloro-N,N-diethylamine hydrochloride,1-(2-chloroethyl)piperidine, 1-(2-chloroethyl)-3,3-dimethylpyrrolidine hydrochloride, 1-(2-chloroethyl)-3-methylpyrrolidine hydrochloride, 1-(3-chloropropyl)piperidine hydrochloride, 1-(3-chloropropyl)hexamethyleneimino hydrochloride, and the like. Preferably, the hydrochloride salt of a formula VIII compound, particularly 2-chloroethylpiperidine hydrochloride, is used.
Generally, one equivalent of formula VIIxe2x80x2 substrate is reacted with 2 equivalents of a formula VIII compound in the presence of at least about 4 equivalents of an alkali metal carbonate, preferably cesium carbonate or potassium carbonate, and an appropriate solvent.
Solvents for this reaction are those solvents or mixture of solvents which remain inert throughout the reaction. N,N-dimethylformamide, especially the anhydrous form thereof, is preferred.
The temperature employed in this step should be sufficient to effect completion of this alkylation reaction. Often, ambient temperature is sufficient and preferred, but in certain cases, higher temperatures may be required.
The present reaction preferably is run under an inert atmosphere, particularly nitrogen.
Under the preferred reaction conditions, this reaction will run to completion in about 16 to about 20 hours. Of course, the progress of the reaction can be monitored via standard chromatographic techniques.
As an alternative for preparing compounds of formulae IXxe2x80x2 or IXxe2x80x3, a formula VIIxe2x80x2 compound is reacted with an excess of an alkylating agent of the formula
Qxe2x80x94(CH2)nxe2x80x94Qxe2x80x2
wherein Q and Qxe2x80x2 each are the same or different leaving group and n is two or three, in an alkali solution. This sequence is illustrated in the first reaction in Scheme III, below. Appropriate leaving groups include the sulfonates such as methanesulfonate, 4-bromobenzenesulfonate, toluenesulfonate, ethanesulfonate, isopropylsulfonate, 4-methoxybenzenesulfonate, 4-nitrobenzenesulfonate, 2-chlorobenzenesulfonate, triflate, and the like, halogens such as bromo, chloro, and iodo, and other related leaving groups. Halogens are preferred leaving groups and bromo is especially preferred.
A preferred alkali solution for this alkylation reaction contains potassium carbonate in an inert solvent such as, for example, methylethyl ketone (MEK) or DMF. In this solution, the 4-hydroxy group of the benzoyl moiety of a formula VIIxe2x80x2 compound exists as a phenoxide ion which displaces one of the leaving groups of the alkylating agent.
This reaction is best when the alkali solution containing the reactants and reagents is brought to reflux and allowed to run to completion. When using MEK as the preferred solvent, reaction times run from about 6 hours to about 20 hours. 
wherein:
R1a, R2a, R3a, R4a, R5, n, and Q have their previous meanings and provisions.
Compounds of formula X would include, but not be limited to:
[2-(3-methoxyphenyl)-6-methoxy-3,4-dihydronaphthalene-1-yl][4-(2-bromoethoxy)phenyl]methanone
[2-(2-methoxyphenyl)-6-methoxy-3,4-dihydronaphthalene-1-yl][4-(2-bromoethoxy)phenyl]methanone
[2-(3-methoxyphenyl)-6-methoxy-3,4-dihydronaphthalene-1-yl][4-(3-bromopropoxy)phenyl]methanone
[2-(3-methoxy-4-fluorophenyl)-6-methoxy-3,4-dihydronaphthalen-1-yl][4-(2-bromoethoxy)phenyl]methanone
[2-(3-chlorophenyl)-6-methoxy-3,4-dihydronaphthalene-1-yl][4-(2-bromoethoxy)phenyl]methanone
[2-(3-methyl-4-methoxyphenyl)-3,4-dihydronaphthalene-1-yl][4-(2-bromoethoxy)phenyl]methanone
[2-(2-chloro-3-methoxyphenyl)-6-methoxy-3,4-dihydronaphthalene-1-yl][4-(2-bromoethoxy)phenyl]methanone,
The reaction product from this step (X) is then reacted with 1-piperidine, 1-pyrrolidine, methyl-1-pyrrolidine, dimethyl-1-pyrrolidine, 4-morpholine, dimethylamine, diethylamine, or 1-hexamethyleneimine, or other secondary amines (R5H), via standard techniques, to form compounds of formula IXxe2x80x2, as seen in the second reaction of Scheme III, supra. Preferably, the hydrochloride salt of piperidine is reacted with the alkylated compound of formula X in an inert solvent, such as anhydrous DMF, and heated to a temperature in the range of from about 60xc2x0 C. to about 110xc2x0 C. When the mixture is heated to a preferred temperature of about 90xc2x0 C., the reaction only takes about 30 minutes to about 1 hour. However, changes in the reaction conditions will influence the amount of time this reaction needs to be run to completion. Of course, the progress of this reaction step may be monitored via standard chromatographic techniques.
An alternative route for preparing compounds of formula IXxe2x80x2 is depicted in Scheme IV, below, wherein R1a, R2a, R3a, R4a, R5, and n have their previous meanings and provisions. 
In this alternative, the starting material is a 1-acylated-2-tetralone of formula XI which already includes the basic side chain moiety. The compound of formula XI is treated with a base to form its corresponding anion, which is reacted with diphenylchlorophosphate, providing an enol phosphate derivative of formula XII. The compound of formula XII undergoes formal addition-elimination when treated with an aryl Grignard reagent (VI), which results in the substitution of the 2-phosphate substituent by the aryl moiety, thereby producing directly a formula IXxe2x80x2 compound.
The compounds of formula XI may be prepared by the methods described in the references, infra. The further reactions outlined in Scheme IV are analogous to those described for Scheme I.
Compounds of formula IXxe2x80x3 would include, but are not limited to.
[2-(3-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone
[2-(3-methoxyphenyl)-3,4-dihydronaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone
[2-(2-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone
[2-(3-methoxyphenyl)3,4-dihydro-6-methoxynaphthalen-1-yl[]4-[2-(1-pyrolidinyl)ethoxy]phenyl]methanone
[2-(3-methoxyphenyl)3,4-dihydro-6-methoxynaphthalen-1-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methanone
[2-(3-methoxy-4-fluorophenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone
[2-(2-methyl-3-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone
[2-(3-chloro-4-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone
[2-(3-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-hexamethylenimino)ethoxy]phenyl]methanone
[2-(3,4-di-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone
Other preferred compounds of formula IX are obtained by cleaving, when present, the R6 hydroxy protecting group of formula IXxe2x80x2 compounds via well known procedures. Such procedures are cited in the references, supra. An exception to these general methods and involves those compounds of formula IXxe2x80x2, wherein R3a bears an oxygen. In the case of these compounds, standard demethylating procedures, such as, the use of Lewis acids, for example, BCl3, AlCl3, PBr3, and the like, leads to the formation of undesired by-products and the desired compounds (IXxe2x80x3) can not be obtained. However, these compounds, wherein R3 is hydroxy may be obtained by cleavage of the methoxy protecting group under basic conditions, such as LiSEt at xe2x88x9270xc2x0 C.
Compounds of formula IXxe2x80x3 would include, but are not limited to:
[2-(3-hydroxyphenyl)-3,4-dihydro-6-hydroxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone
[2-(3-hydroxyphenyl)-3,4-dihydronaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone
[2-(3-methoxyphenyl)-3,4-dihydro-6-hydroxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone
[2-(3-hydroxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone
[2-(3-hydroxyphenyl)-3,4-dihydro-6-hydroxynaphthalen-1-yl][4-[2-(1-pyrolidinyl)ethoxy]phenyl]methanone
[2-(3-hydroxyphenyl)-3,4-dihydro-6-hydroxynaphthalen-1-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methanone
[2-(2-hydroxyphenyl)-3,4-dihydro-6-hydroxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone
[2-(3,4-di-hydroxyphenyl)-3,4-dihydro-6-hydroxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone
[2-(3-hydroxy-4-chlorophenyl)-3,4-dihydro-6-hydroxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone
[2-(2-fluoro-3-hydroxyphenyl)-3,4-dihydronaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone and the like.
The compounds of formula IXxe2x80x2 or IXxe2x80x3 are the starting materials for the next series of reactions for the preparation of compounds of the current invention. In general, the compounds of formula IXxe2x80x2 are most often employed, since any free phenols (IXxe2x80x3) will consume extra reduction reagent.
The compounds of formula IXxe2x80x2 may be converted to formula I compounds via two different reaction sequences. The choice of which sequence to use depends upon the R3 substituent on the pendant phenyl ring. IXbxe2x80x2 compounds, where R3 has an oxygen function, for example, xe2x80x94OH, xe2x80x94OCH3, and the like, may only be converted to formula I compounds by the second reaction sequence (Scheme VI), below. All other IXaxe2x80x2 compounds, wherein R3 is not an oxygen-bearing fuction, may be converted by either sequence, for example, Scheme V or VI.
The first step in both of the above-mentioned synthetic pathways (Scheme V and VI) is the reduction of the bridging carbonyl of the benzoyl moiety to the secondary alcohol (a compound of formula IIIa, wherein R7 is hydroxy). This reduction may be accomplished in a manner similar to that exemplified in U.S. Pat. No. 5,484,795, the disclosure of which is herein incorporated by reference. Briefly, a compound of formula IX is reduced with a hydride reagent, for example, LiAlH4, NaBH4, DIBAL, and the like, in an inert solvent such as ether, THF, toluene, and the like. Such reactions may be carried out at a variety of temperatures from xe2x88x9250 to 50xc2x0 C., generally 0xc2x0 C. to ambient temperature is most convenient and the reaction is complete within two to eighteen hours. This first step yields the compounds of formula IIIa, which are intermediates for the preparation of the compounds formula I, and are useful for the pharmacologic methods of the current invention. Compounds of formula IIIa, would include, but are not limited to:
[2-(3-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanol
[2-(3-methoxyphenyl)-3,4-dihydronaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanol
[2-(2-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanol
[2-(2-methylphenyl)-3,4-dihydronaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanol
[2-(3-methylphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanol
[2-(2-chloro-4-fluorophenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanol
[2-(2,4-di-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanol
[2-(3-methoxyphenyl)3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-pyrolidinyl)ethoxy]phenyl]methanol
[2-(3-methoxyphenyl)3,4-dihydro-6-methoxynaphthalen-1-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methanol
[2-(3-methoxy-4-fluorophenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanol
[2-(2-methyl-3-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanol
[2-(3-chloro-4-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanol
[2-(3-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-hexamethylenimino)ethoxy]phenyl]methanol
[2-(3,4-di-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanol
[2-(3-hydroxyphenyl)-3,4-dihydro-6-hydroxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanol
[2-(3-hydroxyphenyl)-3,4-dihydronaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanol and the like.
A compound of formula IIIa, wherein R3a is not an oxygen-bearing function, may be converted to a compound of formula Ia by protonation of the secondary alcohol with a strong acid, and subsequent, spontanous elimination of water and aromatization of the cyclohexene ring. This sequence is further illustrated in Scheme V, below. 
wherein:
R1a, R2a, R4a, R5, and n have their previous meanings,
R7 is xe2x80x94OH, and
R3c is xe2x80x94H, xe2x80x94Cl, xe2x80x94F, or xe2x80x94C1-C4 alkyl, with the proviso that both R3c and R4a are not both hydrogen.
The chemistry for this transformation of IIIa to Ia is revealed in the references cited, supra. Briefly, a compound of formula IIIa is dissolved in an inert solvent, such as, alkyl esters, alchols, ether, THF, hydrocarbons, halogenated hydrocarbons, and the like, preferred solvents would-be ethylacetate or ethanol. This solution is treated with a molar excess of a strong acid, usually dissolved in the same solvent as the reactant. A two to twenty fold molar excess of the acid is preferred and hydrogen chloride is the preferred acid, other useful acids would be sulfuric, phosphoric, trifuoroacetic, toluenesulfonic, and the like. The reaction may be run at a wide variety of temperatures from xe2x88x9220 to 50xc2x0 C., conveniently ambient temperature is preferred. The reaction is complete almost immediately; however, usually several hours are allowed to elapse. The product may be isolated by standard purification procedures, such as, chromatography using silica gel and eluting solvents such as mixtures of CHCl3 and MeOH or EtOAc-hexanes, and the like.
The compounds of formula Ia would include, but are not limited to:
[2-(2-methoxyphenyl)-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(2,4-di-methoxyphenyl)-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(2-methoxyphenyl)naphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(3-fluorophenyl)-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(3-chlorophenyl)-6-methoxynaphthalen-1-yl][4-[2-(1-pyroidinyl)ethoxy]phenyl]methane
[2-(3-fluoro-4-methoxyphenyl)-6-methoxynaphthalen-1-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methane
[2-(2-methox-3-chlorophenyl)-6-methoxynaphthalen-1-yl][4-[2-(N,N-dimethylamino)ethoxy]phenyl]methane
[2-(2-ethyl-4-chlorophenyl)-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(2-methoxyphenyl)-6-methoxynaphthalen-1-yl][4-[2-(1-hexamethyleneimino)ethoxy]phenyl]methane
[2-(3-ethyl-4-methoxyphenyl)-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(2-methyl-4-chlorophenyl)naphthalen-1-yl][4-[3-(1-(2-methylpyrolidinyl))propoxy]phenyl]methane
[2-(2,4-di-methoxyphenyl)-6-methoxynaphthalen-1-yl][4-[2-(1-(3,3-dimethylpyrolidinyl))ethoxy]phenyl]methane
[2-(2-methyl-4-methoxyphenyl)naphthalen-1-yl][4-[2-(1-pyrolidinyl)ethoxy]phenyl]methane
[2-(2-methyl-3-ethylphenyl)-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(2-ethylphenyl)-6-methoxynaphthalen-1-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methane
[2-(2-methoxy-3-chloro-4-fluorophenyl)-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(2-ethyl-3-chlorophenyl)-6-methoxynaphthalen-1-yl][4-[2-(1-(3-methylpyrolidinyl))ethoxy]phenyl]methane
[2-(2-ethylphenyl)-naphthalen-1-yl][4-[2-(4-morpholino)ethoxy]phenyl]methane
[2-(2-methylphenyl)-6-methoxynaphthalen-1-yl][4-[3-(4-morpholino)propoxy]phenyl]methane and the like.
As mentioned previously, the synthetic route outlined above may be employed for the preparation of the compounds of the current invention with the exception of those with an oxygen function on the 3-position of the pendant phenyl moiety. Attempts at using the dehydration and elimination reaction on compounds of formula III, when R3a is an oxygen-containing fuction, leads to the formation of undesired products. The preparation of compounds of formula Ib, as well as those of formula Ia, is outlined in Scheme VI, below. 
wherein:
R1a, R2a, R3a, R4a, R5, R8, and n have their previous meanings and provisions; and
Z is a sulfonic acid activating moiety, including xe2x80x94Cl, xe2x80x94Br, xe2x80x94N3, or homo/mixed anhydrides.
The preferred starting material for this synthetic sequence is a compound of formula IXxe2x80x2, where any hydroxy functions are protected. Although compounds of formula IXxe2x80x3 may be used, it is not recommended, due to the reactive nature of the hydroxyls with R8OZ.
Compounds of formula IXxe2x80x2 are reduced to their corresponding secondary alcohols (IIIb) in exactly the same manner as discussed, supra. Compounds of formula IIIb are sulfonylated to the compounds of formula IIIc, in order to convert the secondary alcohol to a better leaving group for the subsequent elimination step. This sulfonylation is accomplished by reacting IIIb with R8OZ in the presence of an acid scavenger. Examples of suitable R8OZ compounds would include mesyl chloride, tosyl chloride, propansulfonyl bromide, phenylsulfonyl azide, p-methoxybenzosulfonyl anhydride, ethylsulfonyl-methylsulfonyl anhydride, and the like, preferred is CH3SO2Cl, methanesulfonyl chloride or mesyl chloride. The acid scavenger may be organic or inorganic bases, such as triethylamine, pyridine, lutidines, Na2CO3, Cs2CO3, NaHCO3, and the like, with a preferred base being triethylamine. These reactions are run in inert solvents, such as ether, THF, hydrocarbons, halogenated hydrocarbons, and the like, a preferred solvent would be THF. Further, these reactions may be run at a variety of temperatures from 0xc2x0 to 50xc2x0 C. and are usually complete within one to six hours. The compounds of formula IIIc may be isolated or more conveniently used directly in the next synthetic step. The compounds of formula IIIc are novel and useful for the preparation of the compounds of the current invention (I). The compounds of formula IIIc would include, but not be limited to:
[2-(3-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanoxy methanesulfonate
[2-(3-methoxyphenyl)-3,4-dihydronaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanoxy methanesulfonate
[2-(2-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanoxy tosylate
[2-(2-methylphenyl)-3,4-dihydronaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanoxy n-butanesulfonate
[2-(3-methylphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanoxy methansulfonate
[2-(2-chloro-4-fluorophenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanoxy benzosulfonate
[2-(2,4-di-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanoxy propanesulfonate
[2-(3-methoxyphenyl)3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanoxy methanesulfonate
[2-(3-methoxyphenyl)3,4-dihydro-6-methoxynaphthalen-1-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methanoxy tosylate
[2-(3-methoxy-4-fluorophenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanoxy methansulfonate
[2-(2-methyl-3-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanoxy n-butansulfonate
[2-(3-chloro-4-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanoxy hexanesulfonate
[2-(3-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-hexamethylenimino)ethoxy]phenyl]methanoxy ethanesulfonate
[2-(3,4-di-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanoxy methanesulfonate
[2-(3-hydroxyphenyl)-3,4-dihydro-6-hydroxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanoxy benzosulfonate
[2-(3-hydroxyphenyl)-3,4-dihydronaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanoxy methanesulfonate and the like.
The reaction sequence continues by the conversion of compounds of IIIc to the compounds of formula II by a hydrogen abstraction on the 3 position of the dihydronaphthalene, electron shift, and elimination of the OR8 group. The compounds of formula II are inherently unstable and will thermally rearrange to the compounds of formula Ib. Thus, the compounds of formula II are usually not isolated, but allowed to rearrange to the compounds of the current invention. However, if desired the compounds of formula II may be isolated at low temperatures, especially if temperatures are  less than xe2x88x9250xc2x0 C.
The hydrogen abstraction is accomplished by use of a strong base, for example, a hydride-NaH, LiH, and the like, an alkali metal amide-NaNH2, NaNEt2, and the like, or alkali metal silico-ammoniate-LiN(SiMe3)3, and the like. A preferred reagent would be LiN(SiMe3)3. This reaction is carried out in an inert solvent, such as, ether, THF, hydrocarbons, and the like. THF is the preferred solvent. The reaction may be carried out at a variety of temperatures 0xc2x0 to 50xc2x0 C., most coveniently it is run at ambient temperature. The reaction is complete in two to sixteen hours. As stated before, the compounds of formula II are inherently unstable and will isomerize to the compounds of the current invention (Ib) in about sixteen hours at ambient temperature in THF. If desired the compounds of formula II may be kept at low temperature ( less than xe2x88x9250xc2x0 C.) and in an inert atmosphere, such as nitrogen.
The compounds of formula II are novel and useful in the synthesis of the compounds of the current invention. Compounds of formula II would include, but not be limited to:
[2-(3-methoxyphenyl)-4-hydro-6-methoxynaphthalen-1-ene-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methine
[2-(2-methoxyphenyl)-4-hydro-6-methoxynaphthalen-1-ene-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methine
[2-(3,4-di-methoxyphenyl)-4-hydro-6-methoxynaphthalen-1-ene-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methine
[2-(3-fluorophenyl)-4-hydro-6-methoxynaphthalen-1-ene-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methine
[2-(3-methoxyphenyl)-4-hydro-naphthalen-1-ene-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methine
[2-(3-methoxyphenyl)-4-hydro-6-methoxynaphthalen-1-ene-yl][4-[2-(1-pyrolidinyl)ethoxy]phenyl]methine
[2-(3-methoxyphenyl)-4-hydro-6-methoxynaphthalen-1-ene-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methine
[2-(3-methoxyphenyl)-4-hydro-6-methoxynaphthalen-1-ene-yl][4-[2-(N,N-diethylamino)ethoxy]phenyl]methine
[2-(2-methyl-3-methoxyphenyl)-4-hydro-6-methoxynaphthalen-1-ene-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methine
[2-(3-methoxy-4-chlorophenyl)-4-hydro-6-methoxynaphthalen-1-ene-yl][4-[2-(1-hexamethyleneimino)ethoxy]phenyl]methine and the like.
It should be noted that the compounds of Ia are a subset of Ib and thus the chemistry described in Scheme VI will also enable the preparation of Ia compounds. Compounds of formula Ib would include, but not be limited to:
[2-(3-methoxyphenyl)-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(3,4-di-methoxyphenyl)-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(2,3-di-methoxyphenyl)naphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(3-methoxy-4-fluorophenyl)-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(3-methoxy-4-chlorophenyl)-6-methoxynaphthalen-1-yl][4-[2-(1-pyroidinyl)ethoxy]phenyl]methane
[2-(3-fluoro-4-methoxyphenyl)-6-methoxynaphthalen-1-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methane
[2-(3-methoxyphenyl)-6-methoxynaphthalen-1-yl][4-[2-(N,N-dimethylamino)ethoxy]phenyl]methane
[2-(2-ethyl-3-methoxyphenyl)-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(3-methoxyphenyl)-6-methoxynaphthalen-1-yl][4-[2-(1-hexamethyleneimino)ethoxy]phenyl]methane
[2-(3-methoxy-4-methylphenyl)-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(3-methoxy-4-chlorophenyl)naphthalen-1-yl][4-[3-(1-(2-methylpyrolidinyl))propoxy]phenyl]methane
[2-(2,3,4-tri-methoxyphenyl)-6-methoxynaphthalen-1-yl][4-[2-(1-(3,3-dimethylpyrolidinyl))ethoxy]phenyl]methane
[2-(3-methoxy-4-methoxyphenyl)naphthalen-1-yl][4-[2-(1-pyrolidinyl)ethoxy]phenyl]methane
[2-(2-methyl-3-methoxyphenyl)-6-methoxynaphthalen-1-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methane
[2-(2-ethyl-3-methoxyphenyl)-6-methoxynaphthalen-1-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methane
[2-(2-methyl-3-methoxy-4-fluorophenyl)-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(3-methoxyphenyl)-6-methoxynaphthalen-1-yl][4-[2-(1-(3-methylpyrolidinyl))ethoxy]phenyl]methane
[2-(2-ethyl-3-methoxyphenyl)-naphthalen-1-yl][4-[2-(4-morpholino)ethoxy]phenyl]methane
[2-(2-methyl-3-methoxyphenyl)-6-methoxynaphthalen-1-yl][4-[3-(4-morpholino)propoxy]phenyl]methane and the like.
Other compounds of the current invention (I), wherein R1-4 are acyl, sulfonyl, or carbonate derivatives, for example, compounds of formula Id, are prepared from the hydroxyl compounds Ic. Compounds Ic are prepared from either Ia or Ib by removing the hydroxy protecting group R6. This chemistry is further illustrated in Scheme VII, below. 
Deprotection of the hydroxy functions to form the compounds Ic is discussed in the references cited, supra. Most germane to the removal of the preferred protecting group (wherein R6 is methyl) of the current invention is the reaction of Ia or b with a Lewis acid, for example, BBr3, AlCl3, BCl3, and the like. This reaction is run in an inert solvent, such as ether, THF, halogenated hydrocarbons, and the like, and is run at temperatures from 0xc2x0 to 50xc2x0 C. for one to twenty-four hours. Preferred conditions for the present invention would the use of BBr3 in CH2Cl2 at reflux for three hours. (For a detailed description of this process, see the examples, below.)
The compounds of formula Ic would include, but are not limited to:
[2-(3-hydroxyphenyl)-6-hydroxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(3-hydroxyphenyl)naphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(3-hydroxyphenyl)-6-hydroxynaphthalen-1-yl][4-[2-(1-pyroidinyl)ethoxy]phenyl]methane
[2-(3-hydroxyphenyl)-6-hydroxynaphthalen-1-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methane
[2-(3-methoxyphenyl)-6-hydroxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(3-methoxyphenyl)-6-hydroxynaphthalen-1-yl][4-[2-(1-pyrolidinyl)ethoxy]phenyl]methane
[2-(3-methoxyphenyl)-6-hydroxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(3,4-di-methoxyphenyl)-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(2,3-di-methoxyphenyl)naphthalen-1-yl][4-[2-(4-morpholino)ethoxy]phenyl]methane
[2-(3-methoxyphenyl)-6-hydroxynaphthalen-1-yl][4-[2-(1-hexamethyleneimino)ethoxy]phenyl]methane
[2-(3-methoxy-4-fluorophenyl)-6-hydroxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(3-hydroxy-4-chlorophenyl)-6-methoxynaphthalen-1-yl][4-[2-(1-pyroidinyl)ethoxy]phenyl]methane
[2-(3-fluoro-4-hydroxyphenyl)-6-hydroxynaphthalen-1-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methane
[2-(3-methoxyphenyl)-6-hydroxynaphthalen-1-yl][4-[2-(N,N-dimethylamino)ethoxy]phenyl]methane
[2-(2-ethyl-3-hydroxyphenyl)-6-hydroxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(3-hydroxyphenyl)-6-methoxynaphthalen-1-yl][4-[2-(1-hexamethyleneimino)ethoxy]phenyl]methane
[2-(3-hydroxy-4-methylphenyl)-6-hydroxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(3-hydroxy-4-chlorophenyl)naphthalen-1-yl][4-[3-(1-(2-methylpyrolidinyl))propoxy]phenyl]methane
[2-(2,3,4-tri-hydroxyphenyl)-6-hydroxynaphthalen-1-yl][4-[2-(1-(3,3-dimethylpyrolidinyl))ethoxy]phenyl]methane
[2-(3-hydroxy-4-methoxyphenyl)naphthalen-1-yl][4-[2-(1-pyrolidinyl)ethoxy]phenyl]methane
[2-(2-methyl-3-hydroxyphenyl)-6-hydroxynaphthalen-1-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methane
[2-(2-ethyl-3-methoxyphenyl)-6-hydroxynaphthalen-1-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methane
[2-(2-methyl-3-hydroxy-4-fluorophenyl)-6-hydroxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(3-hydroxyphenyl)-6-hydroxynaphthalen-1-yl][4-[2-(1-(3-methylpyrolidinyl))ethoxy]phenyl]methane
[2-(2-ethyl-3-methoxyphenyl)-naphthalen-1-yl][4-[2-(4-morpholino)ethoxy]phenyl]methane
[2-(2-methyl-3-methoxyphenyl)-6-hydroxynaphthalen-1-yl][4-[3-(4-morpholino)propoxy]phenyl]methane
[2-(2-hydroxyphenyl)-6-hydroxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(2,4-di-hydroxyphenyl)-6-hydroxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(2-hydroxyphenyl)naphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(3-fluorophenyl)-6-hydroxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(3-chlorophenyl)-6-hydroxynaphthalen-1-yl][4-[2-(1-pyroidinyl)ethoxy]phenyl]methane
[2-(3-fluoro-4-methoxyphenyl)-6-hydroxynaphthalen-1-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methane
[2-(2-hydroxy-3-chlorophenyl)-6-hydroxynaphthalen-1-yl][4-[2-(N,N-dimethylamino)ethoxy]phenyl]methane
[2-(2-ethyl-4-chlorophenyl)-6-hydroxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(2-hydroxyphenyl)-6-hydroxynaphthalen-1-yl][4-[2-(1-hexamethyleneimino)ethoxy]phenyl]methane
[2-(3-ethyl-4-hydroxyphenyl)-6-methoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(2-methyl-3-hydroxy-4-chlorophenyl)naphthalen-1-yl][4-[3-(1-(2-methylpyrolidinyl))propoxy]phenyl]methane
[2-(2,4-di-methoxyphenyl)-6-hydroxynaphthalen-1-yl][4-[2-(1-(3,3-dimethylpyrolidinyl))ethoxy]phenyl]methane
[2-(2-methyl-4-hydroxyphenyl)naphthalen-1-yl][4-[2-(1-(pyrolidinyl)ethoxy]phenyl)methane
[2-(2-methyl-3-ethylphenyl)-6-hydroxynaphthalen-1-y][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(2-ethylphenyl)-6-hydroxynaphthalen-1-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methane
[2-(2-hydroxy-3-chloro-4-fluorophenyl)-6-hydroxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(2-ethyl-3-chlorophenyl)-6-hydroxynaphthalen-1-yl][4-[2-(1-(3-methylpyrolidinyl))ethoxy]phenyl]methane
[2-(2-ethylphenyl-4-hydroxy)-naphthalen-1-yl][4-[2-(4-morpholino)ethoxy]phenyl]methane
[2-(2-methylphenyl)-6-hydroxynaphthalen-1-yl][4-[3-(4-morpholino)propoxy]phenyl]methane and the like.
Acyl and sulfonyl compounds (Id) of formula I are prepared by replacing 2xe2x80x2,3xe2x80x2, 4xe2x80x2 and/or 6-position hydroxy moieties of Ic, when present, with a moiety of the formula xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl), xe2x80x94OCAr, where Ar is phenyl or substituted phenyl, xe2x80x94O(CO)O(C1-C6 alkyl) or xe2x80x94Oxe2x80x94SO2xe2x80x94(C2-C6 alkyl) via well known procedures. Such methods are described in U.S. Pat. Nos. 5,393,763 and 5,482,949, the disclosures of which are herein incorporated by reference.
For example, when an xe2x80x94Oxe2x80x94CO(C1-C6 alkyl) group is desired, a mono-, di-, tri, or tetra-hydroxy compound of formula Ia is reacted with an agent such as acyl chloride, bromide, cyanide, or azide, or with an appropriate anhydride or mixed anhydride. The reactions are conveniently carried out in a basic solvent such as pyridine, lutidine, quinoline or isoquinoline, or in a tertiary amine solvent such as triethylamine, tributylamine, methylpiperidine, and the like. The reaction also may be carried out in an inert solvent such as ethyl acetate, dimethylformamide, dimethylsulfoxide, dioxane, dimethoxyethane, acetonitrile, acetone, methyl ethyl ketone, and the like, to which at least one equivalent of an acid scavenger (except as noted below), such as a tertiary amine, has been added. If desired, acylation catalysts such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine may be used. See, for example, Haslam, et al., Tetrahedron, 36:2409-2433 (1980).
The present reactions are carried out at moderate temperatures, in the range from about xe2x88x9225xc2x0 C. to about 100xc2x0 C., frequently under an inert atmosphere such as nitrogen gas. However, ambient temperature is usually adequate for the reaction to run.
Acylation of a 2xe2x80x2,3xe2x80x2, 4xe2x80x2 and/or 6-position hydroxy groups also may be performed by acid-catalyzed reactions of the appropriate carboxylic acids in inert organic solvents. Acid catalysts such as sulfuric acid, polyphosphoric acid, methanesulfonic acid, and the like are used.
The aforementioned R2, R3, and/or R4 groups of formula Id compounds also may be provided by forming an active ester of the appropriate acid, such as the esters formed by such known reagents such as dicyclohexylcarbodiimide, acylimidazoles, nitrophenols, pentachlorophenol, N-hydroxysuccinimide, and 1-hydroxybenzotriazole. See, for example, Bull. Chem. Soc. Japan, 38: 1979 (1965), and Chem. Ber., 788 and 2024 (1970).
Each of the above techniques which provide xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl) moieties are carried out in solvents as discussed above. Those techniques which do not produce an acid product in the course of the reaction, of course, do not call for the use of an acid scavenger in the reaction mixture.
When a formula Id compound is desired in which the 2xe2x80x2,3xe2x80x2, 4xe2x80x2 and/or 6-position hydroxy group of a formula Ic compound is converted to a group of the formula xe2x80x94Oxe2x80x94SO2xe2x80x94(C4-C6 alkyl), the mono-, di-, tri, or tetra-hydroxy compound is reacted with, for example, a sulfonic anhydride or a derivative of the appropriate sulfonic acid such as a sulfonyl chloride, bromide, or sulfonyl ammonium salt, as taught by King and Monoir, J. Am. Chem. Soc., 97:2566-2567 (1975). The hydroxy compounds also can be reacted with the appropriate sulfonic anhydride or mixed sulfonic anhydrides.
Such reactions are carried out under conditions such as were explained above in the discussion of the reaction with acid. halides.
The compounds of formula Id would include, but not be limited to:
[2-(3-acetoxyphenyl)-6-acetoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(3-benzoyloxyphenyl)-6-benzoyloxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(3-n-butylsulfonyloxyphenyl)-6-n-butylsulfonyloxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(3-methoxyphenyl)-6-acetoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(3-methoxyphenyl)-6-benzoyloxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(3-methoxyphenyl)-6-benzoyloxynaphthalen-1-yl][4-[2-(1-pyroidinyl)ethoxy]phenyl]methane
[2-(2-acetoxyphenyl)-6-acetoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(3-acetoxyphenyl)naphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(3-acetoxy-4fluorophenyl)-6-acetoxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane
[2-(2-benzoyloxy-3-chlorophenyl)-6-benzoyloxynaphthalen-1-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane and the like.
Together, the compounds of formula Ia, Ib, Ic, and Id comprise the genus of the compounds of formula I, which are useful for the pharmacological methods described herein.
Although the free-base form of formula I compounds can be used in the methods of the present invention, it is preferred to prepare and use a pharmaceutically acceptable salt form. Thus, the compounds used in the methods of this invention primarily form pharmaceutically acceptable acid addition salts with a wide variety of organic and inorganic acids, and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this invention.
Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, b-hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like. Preferred salts are the hydrochloride and oxalate salts.
The pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of formula with an equimolar or excess amount of acid. The reactants are generally combined in a mutual solvent such as diethyl ether or ethyl acetate. The salt normally precipitates out of solution within about one hour to 10 days and can be isolated by filtration or the solvent can be stripped off by conventional means.
The pharmaceutically acceptable salts generally have enhanced solubility characteristics compared to the compound from which they are derived, and thus are often more amenable to formulation as liquids or emulsions.
The term xe2x80x9csolvatexe2x80x9d represents an aggregate that comprises one or more molecules of the solute, such as a formula I compound, with one or more molecules of solvent. The term xe2x80x9csolvatexe2x80x9d represents an aggregate that comprises one or more molecules of the solute, such as a formula I compound, with one or more molecules of solvent.
The present invention further provides for pharmaceutically acceptable formulations for administering to a mammal, including humans, in need of treatment, which comprises an effective amount of a compound of formula I and a pharmaceutically acceptable diluent or carrier.
As used herein, the term xe2x80x9ceffective amountxe2x80x9d means an amount of compound of the present invention which is capable of inhibiting, alleviating, ameliorating, treating, or preventing further symptoms in mammals, including humans, suffering from estrogen deprivation, for example, menopause or ovariectomy, or inappropriate estrogen stimulation such as uterine fibrosis or endometriosis, or suffering from aortal smooth muscle cell profileration or restenosis. In the case of estrogen-dependent cancers, the term xe2x80x9ceffective amountxe2x80x9d means the amount of compound of the present invention which is capable of alleviating, ameliorating, inhibiting cancer growth, treating, or preventing the cancer and/or its symptoms in mammals, including humans.
By xe2x80x9cpharmaceutically acceptable formulationxe2x80x9d it is meant that the carrier, diluent, excipients and salt must be compatible with the active ingredient (a compound of formula I) of the formulation, and not be deleterious to the recipient thereof. Pharmaceutical formulations can be prepared by procedures known in the art. For example, the compounds of this invention can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, and the like. Examples of excipients, diluents, and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as agar agar, calcium carbonate, and sodium bicarbonate; agents for retarding dissollution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate and solid polyethylene glycols. Final pharmaceutical forms may be: pills, tablets, powders, lozenges, syrups, aerosols, saches, cachets, elixirs, suspensions, emulsions, ointments, suppositories, sterile injectable solutions, or sterile packaged powders, and the like, depending on the type of excipient used.
Additionally, the compounds of this invention are well suited to formulation as sustained release dosage forms. The formulations can also be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time. Such formulations would involve coatings, envelopes, or protective matrices which may be made from polymeric substances or waxes.
The particular dosage of a compound of formula I required to treat, inhibit, or prevent the symptoms and/or disease of a mammal, including humans, suffering from the above maladies according to this invention will depend upon the particular disease, symptoms, and severity. Dosage, routes of administration, and frequency of dosing is best decided by the attending physician. Generally, accepted and effective doses will be from 15 mg to 1000 mg, and more typically from 15 mg to 80 mg. Such dosages will be administered to a patient in need of treatment from one to three times each day or as often as needed for efficacy, normally for at least six months.
The present invention also provides methods for inhibiting estrogen deficient pathologies including, for example, lack of birth control, postmenopausal syndrome including, for example, osteoporosis, cardiovascular disease, restenosis, and hyperlipidemia, certain cancers in men such as protate cancer, acne, hirsutism, dysfunctional uterine bleeding, dysmenorrhea, and atrophic vaginitis comprising administering to a mammal in need of treatment an effective amount of a compound of formula I, and, optionally, an effective amount of a progestin. One of skill in the art will recognize that estrogenic agents have a multitude of applications for treating estrogen deficient pathologies well beyond those listed infra. The present invention contemplates and encompasses such maladies although not specified by name.
Compounds of the current invention may also be used in conjunction with other mixed estrogen agonists/antagonists, especially those which demonstrate increased detrimental stimulation of uterine tissue, such as, for example, tamoxifen, droloxifene, nafoxidene, or clomiphene.
As a further embodiment of the invention, the compounds of formula I may be administered along with an effective amount of an additional therapeutic agent, including but not limited to estrogen, progestin, other benzothiophene compounds including raloxifene, bisphosphonate compounds such as alendronate and tiludronate, parathyroid hormone (PTH), including truncated and/or recombinant forms of PTH such as, for example, PTH (1-34), calcitonin, bone morphogenic proteins (BMPs), or combinations thereof. The different forms of these additional therapeutic agents available as well as the various utilities associated with same and the applicable dosing regimens are well known to those of skill in the art.
Various forms of estrogen and progestin are commercially available. As used herein, the term xe2x80x9cestrogenxe2x80x9d includes compounds having estrogen activity and estrogen-based agents. Estrogen compounds useful in the practice of the present invention include, for example, estradiol estrone, estriol, equilin, equilenin, estradiol cypionate, estradiol valerate, ethynyl estradiol, polyestradiol phosphate, estropipate, diethylstibestrol, dienestrol, chlorotrianisene, and mixtures thereof. Estrogen-based agents, include, for example, 17-xcex1-ethynyl estradiol (0.01-0.03 mg/day), mestranol (0.05-0.15 mg/day), and conjugated estrogenic hormones such as Premarin(copyright) (Wyeth-Ayerst; 0.2-2.5 mg/day). As used herein, the term xe2x80x9cprogestinxe2x80x9d includes compounds having progestational activity such as, for example, progesterone, norethynodrel, norgestrel, megestrol acetate, norethindrone, progestin-based agents, and the like. Progestin-based agents include, for example, medroxyprogesterone such as Provera(copyright) (Upjohn; 2.5-10 mg/day), norethylnodrel (1.0-10.0 mg/day), and norethindrone (0.5-2.0 mg/day). A preferred estrogen-based compound is Premarin(copyright), and norethylnodrel and norethindrone are referred progestin-based agents. The method of administration of each estrogen- and progestin-based agent is consistent with that known in the art.
The formulations which follow are given for purposes of illustration and are not intended to be limiting in any way. The total active ingredients in such formulations comprises from 0.1% to 99.9% by weight of the formulation. The term xe2x80x9cactive ingredientxe2x80x9d means a compound of formula I.
The ingredients are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules.
The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules thus produced are dried at 50-60xc2x0 C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethylcellulose, magnesium stearate, and talc, previously passed through a No. 60 mesh U.S. sieve, are added to the above granules and thoroughly mixed. The resultant material is compressed in a tablet forming machine to yield the tablets.
The active ingredient is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to xe2x88x9230xc2x0 C. and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container.
The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the fatty acid glycerides which had previously heated to their melting point. The mixture is poured into a suppository mold and allowed to cool.
A compound of formula I is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor, and color diluted in water are added and mixture stirred thoroughly. Additional water is added to bring the formulation to final volume.